Influence of volatile anesthetics on thromboxane A2 signaling.
BACKGROUND
Thromboxane A2 (TXA2) is a member of the prostaglandin family; activation of its receptor induces several important effects, including platelet aggregation and smooth muscle contraction. Because volatile anesthetics interfere with aggregation and contraction, the authors investigated effects of halothane, isoflurane, and sevoflurane on TXA2 signaling in an isolated receptor model.


METHODS
mRNA encoding TXA2 receptors was prepared in vitro and expressed in Xenopus oocytes. The effects of halothane, isoflurane, and sevoflurane on Ca2+-activated Cl- currents induced by the TXA2 agonist U-46619 and on those induced by intracellular injection of inositol 1-4-5 trisphosphate or guanosine 5'-O-(2-thiodiphosphate) were measured using the voltage-clamp technique.


RESULTS
Expressed TXA2 receptors were functional (half maximal effect concentration [EC50], 3.2 x 10(-7) +/- 1.1 x 10(-7) M; Hill coefficient (h), 0.8 +/- 0.2). Halothane and isoflurane inhibition of TXA2 signaling was reversible and concentration dependent (halothane half maximal inhibitory concentration [IC50], 0.46 +/- 0.04 mM; h, 1.6 +/- 0.21; isoflurane IC50, 0.69 +/- 0.12 mM; h, 1.3 +/- 0.27). 0.56 mM halothane (1%) right-shifted the U-46619 concentration-response relationship by two orders of magnitude (EC50, 1 x 10[-5] M). That h and maximal effect (Emax) were unchanged indicates that halothane acts in a competitive manner. In contrast, isoflurane acted noncompetitively, decreasing Emax by 30% (h and EC50 were unchanged). Both halothane and isoflurane had no effect on intracellular signaling pathways. Sevoflurane (0-1.3 mM) did not affect TXA2 signaling.


CONCLUSIONS
Both halothane and isoflurane inhibit TXA2 signaling at the membrane receptor, but by different mechanisms. This suggests that the effects of these anesthetics on TXA2 signaling are evoked at different locations of the receptor protein: halothane probably acts at the ligand binding site and isoflurane at an allosteric site.
Hönemann
C W
CW
University of Virginia Health Sciences Center, Charlottesville 22906-0010, USA. cwh@anesthesia.mcc.virginia.edu
Nietgen
G W
GW
Podranski
T
T
Chan
C K
CK
Durieux
M E
ME
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D018118:Chloride Channels / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006221:Halothane / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology; D007530:Isoflurane / Q000494:pharmacology*; D008738:Methyl Ethers / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects; D051381:Rats; D017482:Receptors, Thromboxane / Q000187:drug effects*; D000077149:Sevoflurane; D015398:Signal Transduction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014981:Xenopus
D018685:Anesthetics, Inhalation; D018118:Chloride Channels; D008738:Methyl Ethers; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; D000077149:Sevoflurane; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D006493:Heparin; D007530:Isoflurane; D006221:Halothane